Discovery of the central nervous system mechanisms by which drugs influence behavior is important in understanding the basic processes in brain and behavior in general, and more practically because it establishes the knowledge base for the development of medications to treat dependence, as well as identifying potential substrates for biological variability. Studies of the reinforcing effects of drugs have identified that a particular population of dopamine neurons located in the ventral part of the midbrain (ventral tegmental area, VTA) play a major role in drug-taking behavior. However, these dopamine systems are not uniquely involved in drug-taking behavior, but also subserve other motivated behaviors and motor functions. The approach taken in this research is to discover other neuronal systems which likely regulate these dopamine neurons and hence influence drug-taking behavior. Our hypothesis has two parts. First, we propose that the activation of mu opioid receptors in the VTA can have different effects on the self-administration of non-opioid drugs like nicotine and cocaine, depending on the extent of recruitment of GABAergic elements in the VTA by the drug in question. Second, we propose that cholinergic projections from the mesopontine area to the VTA play a role in drug reinforcement when they are activated. This preclinical research uses techniques in which animals are trained to do work (press a lever) to obtain intravenous infusions of nicotine or cocaine. Brain pathways and mechanisms are identified by manipulating the drug-taking behavior with neurochemical lesions of particular neuronal pathways in the brain, or by microinfusions of neurochemicals into certain brain areas. Conceptually the experiments proposed to test the first part of the hypothesis build on the observation that the focal administration of a mu-selective opioid agonist into the VTA alters cocaine self-administration more than nicotine self-administration. Experiments in this application will test whether this observation reflects an effect on the ability of the self-administered drug to reinforce behavior, and whether GABAergic mechanisms are involved. The second part of our hypothesis derives from studies which have shown that selective lesions of the cholinergic cells of the caudal part of the pedunculopontine tegmental nucleus (PPTg), which provide cholinergic input to the VTA, or blocking the effects of nicotine in the PPTg with a nicotinic antagonist, reduce nicotine self-administration. Experiments will examine whether depleting this population of cholinergic cells produces a selective effect on nicotine versus cocaine reinforcement, and whether agents that alter the activity of these cholinergic cells affect reinforcement more generally.